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Roles of the Mammalian Mitochondrial Fission and Fusion Mediators Fis1, Drp1, and Opa1 in Apoptosis
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During apoptosis, the mitochondrial network fragments. Using short hairpin RNAs for RNA interference, we manipulated the expression levels of the proteins hFis1, Drp1, and Opa1 that are involved in mitochondrial fission and fusion in mammalian cells, and we characterized their functions in mitochondrial morphology and apoptosis. Down-regulation of hFis1 powerfully inhibits cell death to an extent significantly greater than down-regulation of Drp1 and at a stage of apoptosis distinct from that induced by Drp1 inhibition. Cells depleted of Opa1 are extremely sensitive to exogenous apoptosis induction, and some die spontaneously by a process that requires hFis1 expression. Wild-type Opa1 may function normally as an antiapoptotic protein, keeping spontaneous apoptosis in check. However, if hFis1 is down-regulated, cells do not require Opa1 to prevent apoptosis, suggesting that Opa1 may be normally counteracting the proapoptotic action of hFis1. We also demonstrate in this study that mitochondrial fragmentation per se does not result in apoptosis. However, we provide further evidence that multiple components of the mitochondrial morphogenesis machinery can positively and negatively regulate apoptosis.
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“A decrease in mitochondrial fusion caused by reduced levels of Opa1 can also influence the progression of cell-death pathways (Lee et al., 2004; Olichon et al., 2003).”
From New insights into the role of mitochondria in aging: mitochondrial dynamics and more (2010) · cites this paper as Lee et al., 2004
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Metadata
- Authors
- Lee, Y.-J., Jeong, S.-Y., Karbowski, M., Smith, C. L., & Youle, R. J.
- Affiliations
- National Institutes of Health (US)
- Venue
- Molecular Biology of the Cell
- Published
- 2004-11
- Volume
- 15
- Issue
- 11
- Pages
- 5001-5011
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC524759
- OpenAlex
- W1970248089
- Cited by
- 1,042
- References
- 49
- Citations by year
- 2026: 15 · 2025: 20 · 2024: 41 · 2023: 39 · 2022: 43 · 2021: 50 · 2020: 52 · 2019: 36 · 2018: 54 · 2017: 40 · 2016: 72 · 2015: 55 · 2014: 47 · 2013: 50 · 2012: 74
- FWCI
- 14.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Biology of the Cell (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- AJOU Open Repository (Ajou University) (submittedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Institute of Neurological Disorders and Stroke
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- apoptosis, mitochondrial fission, mitochondrial fusion, Fis1, Drp1, OPA1, mitochondrial morphology, mitochondrial fragmentation, anti-apoptotic proteins, spontaneous apoptosis, mitochondrial morphogenesis
- MeSH terms
- HeLa Cells, Humans, Immunohistochemistry, Membrane Proteins, Microtubule-Associated Proteins, Mitochondria, Poly(ADP-ribose) Polymerases, RNA, Subcellular Fractions, Time Factors, Immunoblotting, Down-Regulation, Apoptosis, Microscopy, Confocal, GTP Phosphohydrolases, Mitochondrial Proteins, Dynamins, RNA Interference
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